Over the past several years the applicants have developed a novel hypothesis to help explain the pathophysiology of Alzheimer's disease (AD) that removes around the concept of NMDA receptor hypofunction (NRHYPO). NRHypo is a state that can be induced experimentally in the adult rat brain by treatment with drugs that block NMDA glutamate receptors. A sustained blockade of NMDA receptors lasting for many hours triggers a neurodegenerative reaction in the adult rat brain which is irreversible and affects many of the same neuronal populations and brain regions that are affected in AD. The potential relevance of the NRHypo mechanism to AD is enhanced by evidence that in the normal aging brain the NMDA receptor system becomes progressively impaired (hypofunctional), and is even more hypofunctional in the brains of AD patients than in age matched controls. Relevance of the NRHypo mechanism to AD is also potentially supported by other lines of preliminary of evidence that potentially link the NRHypo mechanism to the neuropathology of AD. In Aim 1, we will apply electron microscopic and immunocytochemical methods to evaluate neurodegenerative changes in biopsy specimens from human AD brains and determine what extent these changes resemble those associated with the NRHYPO state in the adult rat brain. In Aim 2, we will study pathomorphological changes in the brains of transgenic amyloid over-expressing mice, in which we will pharmacologically induce an NRHYPO state, the goal being to test the hypothesis that the combined presence of amyloidopathy and NRHypo neurodegeneration in the same animal brain may produce AD-like pathomorphological changes not seen in either the transgenic or NRHYPO condition alone. In Aim 3, we will test a hypothesis pertaining to the sequence with which different neuronal populations degenerate in AD, the main postulation being that by an excitotoxic mechanism basal forebrain cholinergic neurons contribute to the demise of cerebrocortical neurons that they innervate, and that the cerebrocortical target neurons degenerate first and cholinergic neurons second, perhaps due to loss of trophic support from the cerebrocortical neurons. In Aim 4, we will explore preliminary evidence that female rats become resistant to NRHYPO neurodegeneration during pregnancy when circulating levels of estrogen and progesterone are very high, and will test the hypothesis that a neuroprotective effect of one or both of these sex hormones is responsible for the observed resistance to NRHYPO neurodegeneration.